Abstract
Aim The protection against ischemia/reperfusion injury mediated by remote limb ischemic postconditioning (RIPC) shows great clinical value in ischemic stroke therapy, but the particular mechanism of RIPC remains unclear. Methods We carried out middle cerebral artery occlusion/reperfusion (MCAO/R) surgery on C57BL/6 male mice. RIPC was generated by 10-minute occlusion followed by the same period of reperfusion of the bilateral hind limb femoral artery and repeated for 3 cycles. Infarct size and neurological score were performed to assess stroke outcomes. Ly6Chi monocytes were quantified in the blood and brain by flow cytometry. Real-time PCR, ELISA, and immunofluorescence were utilized to detect phenotype of proinflammatory M1 and anti-inflammatory M2 microglia/macrophage. Nuclear factor κB (NF-κB) and peroxisome proliferator-activated receptor γ (PPARγ) levels were detected using Western blot. Results At 24 and 72 h after MCAO, RIPC drastically attenuated infarct size and ameliorated the neurological deficits of mice and facilitated transmigration of Ly6Chi monocytes to the brain postischemia reperfusion. Furthermore, RIPC contributed to increased M2 and reduced M1 microglia/macrophage through inhibiting NF-κB and promoting PPARγ activation. Conclusion Our results reveal pharmacological effect of RIPC in promoting microglia/macrophage transferring from M1 to M2 phenotype after MCAO/R in mice, which provides theoretical support for the therapeutic effect of RIPC in ischemic stroke.
Highlights
Despite significant advances in medical and surgical intervention, ischemic stroke is still a prominent source of death and long-term disability globally
We explored the therapeutic efficacy of Remote limb ischemic postconditioning (RIPC) by identifying the inflammatory cytokines and M1/M2 polarization markers that are present in the cortex of middle cerebral artery occlusion/reperfusion (MCAO/R) mice and investigated whether the neuroprotective effect is associated with the Nuclear factor κB (NF-κB) and peroxisome proliferator-activated receptor γ (PPARγ) pathway
RIPC repressed NF-κB shifting from the cytoplasm to the nucleus and stimulated PPARγ shifting from the nucleus to the cytoplasm
Summary
Despite significant advances in medical and surgical intervention, ischemic stroke is still a prominent source of death and long-term disability globally. In M1 microglia/macrophage, nuclear factor κB (NF-κB) activation may facilitate the expression of proinflammatory cytokines, leading to neurotoxic outcomes [6]. Swapping microglia/macrophage from an M1 to an M2 phenotype may represent an efficacious treatment strategy for ischemic stroke therapy. Several researches have shown that activating PPARγ signaling leads to a reduction in inflammation which is related to regulation of the M1/M2 phenotype in Alzheimer’s disease and experimental stroke [9, 12]. We explored the therapeutic efficacy of RIPC by identifying the inflammatory cytokines and M1/M2 polarization markers that are present in the cortex of middle cerebral artery occlusion/reperfusion (MCAO/R) mice and investigated whether the neuroprotective effect is associated with the NF-κB and PPARγ pathway
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